Viral infection contributes to nearly 15% of human cancers worldwide. Many of the oncogenic viruses are prone to cause cancer in immunosuppressed individuals but maintain asymptomatic infection in the general population, underscoring the critical role of the host immune system in preventing oncogenic virus-induced cancers. The importance of host immunity is clearly demonstrated in Merkel cell polyomavirus (MCPyV) and associated cancers. MCPyV is a novel human polyomavirus that has been shown to cause Merkel cell carcinoma (MCC). MCC is one of the most aggressive skin cancers with a disease-associated mortality rate between 33-46% that exceeds the rate of melanoma and less than 45% five-year survival rate. While the incidence of MCC has tripled over the past twenty years, there is no effective chemotherapy available for metastatic MCC. MCPyV infection is widespread in the general population, suggesting that the virus has evolved a mechanism to evade host immune eradication. Immune suppression is one of the most important risk factors for MCPyV-associated MCC, indicating that failure of human hosts to control MCPyV infection can increase the likelihood of MCPyV-related tumorigenesis. In immune competent patients, MCC tumor continues to develop despite the production of T cells recognizing MCPyV-encoded proteins. Recently developed immunotherapies showed promising results but the responses are short-lived. The abilities of MCPyV- associated MCCs to escape immunological destruction and to resist immunotherapy argue that this virus-induced tumorigenesis is empowered by an immune evasion mechanism. Identification of immune effectors that normally restrict MCPyV propagation may reveal mechanism for MCPyV oncogenesis and inform strategies to reduce its disease burden. However, very little in known about how MCPyV interacts with the immune system. This topic was impossible to study because MCPyV tropism was previously unknown, making it technically difficult to cultivate MCPyV. We recently identified human dermal fibroblasts as the host cells for MCPyV and established the first cell infection model for this oncogenic virus. Using this system, we observed, for the first time, the induction of immune gene expression triggered by MCPyV infection. In this grant, we will determine the molecular mechanisms by which MCPyV induces immune response (Aim 1) and characterize this response genome-wide using the ex vivo skin culture that mimics the physiological environment of the human skin (Aim 2). Through revealing the largely unknown interplay between MCPyV and the host immune system, our goal is to understand how immunoevasion contributes to MCPyV persistence and MCC oncogenesis. Elucidating specific aspects of host immunity that normally restrict MCPyV infection could unveil novel strategies for preventing and treating the devastating MCC cancer.